For convenience, reference publications relating to or mentioned in the following description are numerically labelled and listed in the appended bibliography.
The invention has its origins in research carried out in connection with cancer cachexia. Cancer cachexia is a common condition in many human cancer patients, especially patients with gastrointestinal or lung cancer, and is characterised by progressive weakness, dramatic weight loss and wasting resulting from loss of both adipose tissue and skeletal muscle mass. Previous investigations have indicated that the characteristic loss of weight and body tissues (fat and muscle) cannot usually be explained simply by a reduction of food and water intake, and the effect has been attributed to production by the tumours of catabolic factors that pass into the circulatory system. Both lipolytic and proteolytic activities are involved, and there have been numerous attempts to isolate and purify the substances that produce these activities, especially lipid mobilising factors responsible for the catabolism of adipose tissue and reduction of carcass fat.
In GB2217330A, for example, the supposed isolation and purification was described of lipolytic factors derived from a cachexia-inducing murine tumour designated MAC16 and also from the urine of cachectic cancer patients using chromatographic methods which included at least one stage of gel filtration exclusion chromatography, and results were obtained that suggested there were several related molecular species having an apparent molecular weight less than 5000 daltons that were responsible for the lipolytic effect. Severe problems were encountered, however, in attempting to purify the active molecular species to the extent required for use in therapeutic applications and fully to characterise the active material in terms of its chemical constitution. More recently, in 1995, a paper by T. M. McDevitt et al., entitled “Purification and characterisation of a lipid-mobilising factor associated with cachexia-inducing tumours in mice and humans”, was published in Cancer Research 55, 1458-1463 (reference 1), wherein it was reported that a material having an apparent relative molecular mass Mr of 24 kDa had been isolated from both the above-mentioned cachexia-inducing murine tumour MAC16 and from the urine of patients with cancer cachexia using an isolation and purification procedure involving a combination of ion exchange, size exclusion and hydrophobic chromatography, and a belief was expressed that this material was a purified form of cancer cachexia lipid mobilising factor. It was subsequently found, however, that this 24 kDa material was in fact a proteoglycan which when purified to homogeneity would produce a cachectic state in non-tumour bearing mice by inducing catabolism of skeletal muscle protein, as reported by P. Todorov et al. 1996, Nature, 379, 739-742 (reference 2). Thus, this 24 kDa material was a proteolytic factor and it seems that any lipolytic activity had to be attributed to contamination through co-purification with a separate and distinct lipolytic factor.